Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest
Cardiac arrest (CA) causes high mortality due to multi-system organ damage attributable to ischemia-reperfusion injury. Recent work in our group found that among diabetic patients who experienced cardiac arrest, those taking metformin had less evidence of cardiac and renal damage after cardiac arres...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-06-01
|
| Series: | Journal of Molecular and Cellular Cardiology Plus |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976123000041 |
| _version_ | 1827370878513446912 |
|---|---|
| author | Cody A. Rutledge Claudia Lagranha Takuto Chiba Kevin Redding Donna B. Stolz Eric Goetzman Sunder Sims-Lucas Brett A. Kaufman |
| author_facet | Cody A. Rutledge Claudia Lagranha Takuto Chiba Kevin Redding Donna B. Stolz Eric Goetzman Sunder Sims-Lucas Brett A. Kaufman |
| author_sort | Cody A. Rutledge |
| collection | DOAJ |
| description | Cardiac arrest (CA) causes high mortality due to multi-system organ damage attributable to ischemia-reperfusion injury. Recent work in our group found that among diabetic patients who experienced cardiac arrest, those taking metformin had less evidence of cardiac and renal damage after cardiac arrest when compared to those not taking metformin. Based on these observations, we hypothesized that metformin's protective effects in the heart were mediated by AMPK signaling, and that AMPK signaling could be targeted as a therapeutic strategy following resuscitation from CA. The current study investigates metformin interventions on cardiac and renal outcomes in a non-diabetic CA mouse model. We found that two weeks of metformin pretreatment protects against reduced ejection fraction and reduces kidney ischemia-reperfusion injury at 24 h post-arrest. This cardiac and renal protection depends on AMPK signaling, as demonstrated by outcomes in mice pretreated with the AMPK activator AICAR or metformin plus the AMPK inhibitor compound C.At this 24-h time point, heart gene expression analysis showed that metformin pretreatment caused changes supporting autophagy, antioxidant response, and protein translation. Further investigation found associated improvements in mitochondrial structure and markers of autophagy. Notably, Western analysis indicated that protein synthesis was preserved in arrest hearts of animals pretreated with metformin. The AMPK activation-mediated preservation of protein synthesis was also observed in a hypoxia/reoxygenation cell culture model. Despite the positive impacts of pretreatment in vivo and in vitro, metformin did not preserve ejection fraction when deployed at resuscitation. Taken together, we propose that metformin's in vivo cardiac preservation occurs through AMPK activation, requires adaptation before arrest, and is associated with preserved protein translation. |
| first_indexed | 2024-03-08T10:28:59Z |
| format | Article |
| id | doaj.art-e1a713b4f1ec4938b59f75d481a7de4c |
| institution | Directory Open Access Journal |
| issn | 2772-9761 |
| language | English |
| last_indexed | 2024-03-08T10:28:59Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj.art-e1a713b4f1ec4938b59f75d481a7de4c2024-01-27T07:02:33ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612023-06-014100034Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrestCody A. Rutledge0Claudia Lagranha1Takuto Chiba2Kevin Redding3Donna B. Stolz4Eric Goetzman5Sunder Sims-Lucas6Brett A. Kaufman7Division of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author at: 200 Lothrop Street, BST E1241, Pittsburgh, PA 15261, USA.Division of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USARangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA; Division of Nephrology, Department of Pediatrics, University of Pittsburgh School, Pittsburgh, PA, USADivision of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USADepartment of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USARangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA; Division of Nephrology, Department of Pediatrics, University of Pittsburgh School, Pittsburgh, PA, USADivision of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USACardiac arrest (CA) causes high mortality due to multi-system organ damage attributable to ischemia-reperfusion injury. Recent work in our group found that among diabetic patients who experienced cardiac arrest, those taking metformin had less evidence of cardiac and renal damage after cardiac arrest when compared to those not taking metformin. Based on these observations, we hypothesized that metformin's protective effects in the heart were mediated by AMPK signaling, and that AMPK signaling could be targeted as a therapeutic strategy following resuscitation from CA. The current study investigates metformin interventions on cardiac and renal outcomes in a non-diabetic CA mouse model. We found that two weeks of metformin pretreatment protects against reduced ejection fraction and reduces kidney ischemia-reperfusion injury at 24 h post-arrest. This cardiac and renal protection depends on AMPK signaling, as demonstrated by outcomes in mice pretreated with the AMPK activator AICAR or metformin plus the AMPK inhibitor compound C.At this 24-h time point, heart gene expression analysis showed that metformin pretreatment caused changes supporting autophagy, antioxidant response, and protein translation. Further investigation found associated improvements in mitochondrial structure and markers of autophagy. Notably, Western analysis indicated that protein synthesis was preserved in arrest hearts of animals pretreated with metformin. The AMPK activation-mediated preservation of protein synthesis was also observed in a hypoxia/reoxygenation cell culture model. Despite the positive impacts of pretreatment in vivo and in vitro, metformin did not preserve ejection fraction when deployed at resuscitation. Taken together, we propose that metformin's in vivo cardiac preservation occurs through AMPK activation, requires adaptation before arrest, and is associated with preserved protein translation.http://www.sciencedirect.com/science/article/pii/S2772976123000041MetforminCardiac arrestAMPKMyocardial stunning |
| spellingShingle | Cody A. Rutledge Claudia Lagranha Takuto Chiba Kevin Redding Donna B. Stolz Eric Goetzman Sunder Sims-Lucas Brett A. Kaufman Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest Journal of Molecular and Cellular Cardiology Plus Metformin Cardiac arrest AMPK Myocardial stunning |
| title | Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| title_full | Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| title_fullStr | Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| title_full_unstemmed | Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| title_short | Metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| title_sort | metformin preconditioning protects against myocardial stunning and preserves protein translation in a mouse model of cardiac arrest |
| topic | Metformin Cardiac arrest AMPK Myocardial stunning |
| url | http://www.sciencedirect.com/science/article/pii/S2772976123000041 |
| work_keys_str_mv | AT codyarutledge metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT claudialagranha metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT takutochiba metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT kevinredding metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT donnabstolz metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT ericgoetzman metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT sundersimslucas metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest AT brettakaufman metforminpreconditioningprotectsagainstmyocardialstunningandpreservesproteintranslationinamousemodelofcardiacarrest |